PROJECT SUMMARY Cancer-related cognitive impairment (CRCI) is a devastating condition, affecting 3 in 4 breast cancer survivors. Non-pharmacologic interventions (e.g. exercise, cognitive training) demonstrated preliminary effects for CRCI, but their specific efficacies need to be confirmed in larger, rigorous trials using active/attention controls. More importantly, given the multi-faceted etiology and presentation of CRCI, it is unlikely that a single therapy is optimal for all patients; thus, there remains a critical need to test novel interventions and personalize treatment. Acupuncture has a growing evidence base in cancer symptom management, but its role in treating CRCI remains unclear. In animal models, acupuncture has been shown to modulate hippocampal expression of brain-derived neurotrophic factor (BDNF), an important cognitive biomarker. A Chinese study (N=80) found that acupuncture improved cognitive function and increased serum BDNF in breast cancer patients compared to usual care, but findings were limited by small sample size and lack of sham control, thus precluding evaluation of specific efficacy. In secondary analyses of our recent comparative effectiveness trial (N=160) of acupuncture versus cognitive-behavioral therapy for insomnia (CBT-I), acupuncture significantly improved subjective insomnia as well as perceived and objective cognitive functions, suggesting that targeting sleep improves cognition. Acupuncture also significantly increased serum BDNF, particularly among those with low baseline levels, whereas CBT-I did not. This suggests that BDNF is a specific mechanism by which acupuncture influences cognition and could help to identify individuals most likely to respond to acupuncture, thereby personalizing therapy. Based on this data, our central hypothesis is that acupuncture is an efficacious treatment for CRCI that works through a mechanism involving BDNF and sleep. Building on this work, we bring together a multi-disciplinary team to propose the Effect and Mechanism of Acupuncture for Cancer-related Cognitive Impairment (ENHANCE) trial. We found that nearly 80% of breast cancer survivors with CRCI report insomnia, echoing the growing research on connections between cognition and sleep. Thus, we will recruit 260 breast cancer survivors with CRCI and insomnia and randomize them to one of 3 conditions in an RCT: 1) acupuncture, 2) sham acupuncture (SA), or 3) usual-care wait-list control (WLC). We will collect serum BDNF and patient-reported/objective measures of cognition and sleep from baseline to Week 26. The Specific Aims are 1) to determine the effects of acupuncture on perceived CRCI and objective cognitive function; 2) to evaluate the mechanism of acupuncture on perceived CRCI and objective cognitive function via BDNF; and 3) to elucidate the role of insomnia on perceived CRCI and objective cognitive function in context of acupuncture. If successful, our study would expand treatment options for CRCI, advance mechanistic understanding of acupuncture, and disentangle the relationship between sleep and cognition, helping to shift the treatment paradigm towards a personalized model that targets CRCI phenotypes based on BDNF profile and insomnia.